Nuclear protein in testis gene

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The nuclear protein in testis gene (i.e. NUTM1 gene) encodes (i.e. directs the synthesis of) a 1,132-amino acid protein termed NUT [1] that is expressed almost exclusively in the testes, ovaries, [2] and ciliary ganglion (i.e. a parasympathetic ganglion of nerve cells located just behind the eye). [3] NUT protein facilitates the acetylation of chromatin (i.e. DNA-protein bundles) by histone acetyltransferase EP300 in testicular spermatids (cells that mature into sperms). This acetylation is a form of chromatin remodeling which compacts spermatid chromatin, a critical step required for the normal conduct of spermatogenesis, i.e. the maturation of spermatids into sperm. [4] Male mice that lacked the mouse Nutm1 gene using a gene knockout method had abnormally small testes, lacked sperm in their cauda epididymis (i.e. tail of the epididymis which contains sperm in fertile male mice), and were completely sterile. [5] These findings indicate that Nutm1 gene is essential for the development of normal fertility in male mice and suggest that the NUTM1 gene may play a similar role in men. [1] [5]

Contents

The NUTM1 gene is located in band 14 on the long (or "q") arm of chromosome 15. In the early 1990s, this gene was implicated in the development of certain epithelial cell cancers that: a) occurred in the midline structures of young people, b) were rapidly fatal, and c) consisted of poorly differentiated (i.e. not resembling any particular cell type), immature-appearing cells containing a BRD4-NUTM1 fusion gene. BRD4 is the bromodomain-containing protein 4 gene. A fusion gene is an abnormal gene consisting of parts from two different genes that form as a result of a large scale gene mutation such as a chromosomal translocation, interstitial deletion, or inversion. The BRD4-NUTM1 fusion gene is a translocation that encodes a fusion protein that has merged most of the protein coding region of the NUTM1 gene with a large part of the BRD4 gene located in band 13 on the short (i.e. "q") arm of chromosome 19. This translocation is notated as t(15;19)(q13, p13.1). [2]

BRD4 protein recognizes acetylated lysine residues on proteins and by doing so participates in the regulation of DNA replication, DNA transcription, and thereby key cellular processes involved in the development of neoplasms (i.e. malignant or benign tissue growths). [6] The product of the BRD4-NUTM1 fusion gene, BRD4-NUT protein, stimulates the expression of at least 4 relevant genes, MYC, TP63, SOX2, [4] and MYB [7] in cultured cells. All four of these genes are oncogenes, i.e., genes that when overexpressed and/or overly active promote the development of certain types of cancers. Overexpression of the MYC and SOX2 genes can also act to maintain cells in an undifferentiated stem cell-like state similar to the cells in the neoplasms driven by the BRD4-NUTM1 fusion gene. It is generally accepted that the BRD4-NUT protein promotes these neoplasms by maintaining their neoplastic cells in a perpetually undifferentiated, proliferative state. [4] Further studies are needed to confirm and expand these views and to determine if any of the overexpressed gene products of the BRD4-NUT protein contribute to the development and/or progression, or can serve as targets for the treatment, of the neoplasms associated with the BRD4-NUTM1 fusion gene. These questions also apply to a wide range of neoplasms that have more recently been associated with the NUTM1 gene fused to other genes. [4] [7]

Neoplasms associated with NUTM1 fusion genes

NUT carcinoma

NUT carcinoma is a rare, highly aggressive malignancy. Initially, it was regarded as occurring in the midline areas of the upper respiratory tract, upper digestive tract, and mediastinum (i.e. central compartment of the thoracic cavity) of young adults and to lesser extents children and infants. It was therefore termed NUT midline granuloma. However, subsequent studies defined these carcinomas based on the presence of a NUT fusion gene in their malignant cells. As so defined, this malignancy occurs in individuals of all ages and, while most commonly developing in the cited respiratory, gastrointestinal, and mediastinal areas, occasionally develops in the salivary glands, pancreas, urinary bladder, retroperitoneum (i.e. space behind the peritoneum of the abdominal cavity), [8] endometrium, kidneys, ovaries, and other organs. [9] Consequently, the name of this disorder was changed form NUT midline carcinoma to NUT carcinoma by the World Health Organization, 2015. [10] NUT carcinomas are characterized histologically as tumors containing primitive epithelioid cells (i.e. derived from activated macrophages and resembling epithelial cells) admixed with foci of keratinization (i.e. tissue areas that are rich in keratin fibers); NUT carcinomas are considered variants of squamous cell carcinomas. [11] Studies have found that ~66 tp 80% of NUT carcinomas harbor a BRD4-NUTM1 fusion gene while the remaining NUT carcinomas, sometimes termed NUT variant carcinomas, involve the BRD3-NUTM1 (~10 to 25% of cases) [1] [12] or, rarely, the NSD3-NUTM1, ZNF532-NUTM1,, or ZNF592-NUTM1 fusion gene. It is thought that the latter fusions genes promote NUT carcinomas in manners at least somewhat similar to the BRD4-NUTM1 fusion gene. [1]

Acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is a blood cancer of malignant B lymphocytes (termed B-cell ALL) or T lymphocytes (termed T-cell ALL) that typically occurs in infants and young children. In a three population-representative cohort study, NUTM1 gene rearrangements (i.e. fusion genes) occurred in 0.28 to 0.86% of pediatric patients with B-cell ALL. Among a total of 71 NUTM1-rearranged cases, 10 fusion partners of NUTM1 were identified: ACIN1-NUTM1 (24 cases), BRD9-NUTM1 (10 cases), CUX1-NUTM1 (15 cases), ZNF618-NUTM1 (9 cases; ZNF618 is the zinc finger protein 618 gene) fusion genes, and (in 1 to 4 cases each) AFF1-NUTM1, C17orf78-NUTM1 (C17orf78 is also termed ATAD5), CHD4-NUTM1, RUNX1-NUTM1, IKZF1-NUTM1, and SLC12A6-NUTM1 fusion genes. [13] Individuals with these NUTM1 fusion gene-associated leukemias had appreciably better prognoses than those who had NUTM1 fusion gene negative B-cell acute lymphoblastic leukemias. [13] It is thought that the cited fusion genes contribute to the development and/or progression of these NUTM1 fusion gene-associated ALL cases but the molecular mechanism(s) for this is unknown. Some HOXA genes, particularly HOXA9, are upregulated [ broken anchor ] in these NUTM1 fusion gene-associated ALL cases [14] as well as in cases of NUTM1 fusion gene-negative ALL. [15] Further studies are required to determine if the overexpression of one or more HOXA genes contributes to NUTM1 fusion gene-associated B-cell ALL. [14]

Poroma and porocarcinoma

Poroma is a benign, relatively common skin tumor that has the cellular features similar to those of a sweat gland duct. This tumor typically occurs as a solitary stalkless nodule on the soles and palms but may occur in any area where there are sweat glands. Porocarcinoma (also termed eccrine porocarcinoma and malignant eccrine poroma) is an extremely rare malignant counterpart of poromas. It may arise from a longstanding poroma but more commonly appears to develop independently of any precursor poroma. Porocarcinoma tumors predominantly afflict elderly individuals. A study of 104 poroma tumors detected the YAP1-NUTM1 and WWTR1-NUTM1 fusion genes in 21 cases and 1 case, respectively, while the same study of 11 porocarcinoma tumors detected the YAP1-NUTM1 fusion gene in 6 cases. Expression of the NUTM1 (fusion) protein was observed in 25 poroma and 6 porocarcinoma cases but not in a wide range of other skin tumor types. Studies on cultured immortalized human dermal keratinocyte (i.e. HDK) and mouse embryonic fibroblast NIH-3T3 cell lines found that the YAP1-NUTM1 and WWTR1-NUTM1 fusion genes stimulated the anchorage-independent growth of NIH-3T3 cells and activated a transcriptional enhancer factor family member (i.e. TEAD family) reporter gene. [16] The TEAD family in mammals includes four members, TEAD1, TEAD2, TEAD3, and TEAD4 that are transcription factors, i.e. proteins that regulate the expression of various genes. TEAD family proteins have been found to promote the development, progression, and/or metastasis of various cancer types [17] [18] and, based on the studies just cited, [17] are thought to do so in poromas and porocarcinomas. However, further studies are needed to confirm this association and determine if TEAD family transcription factors may be useful targets for treating the porocarcinomas. [1] [16] [17] [18]

Sarcomas

In addition to the NUTM1 fusion genes in the above cited carcinomas, recent studies have found NUTM1 fusion genes in malignancies with undifferentiated spindle cell, round cell, and epithelioid cell-like features which are regarded as sarcomas. [11] Sarcomas with NUTM1 fusion genes typically a) occur in some sites were sarcomas otherwise rarely develop and b) consist of tumor cells that express a NUTM1 gene fused to one of the MADS-box gene family genes (i.e. a MXD4, MGA , or MXD1 gne), or, alternatively, a BRD4, ZNF532, or CIC gene. [12] A recent review listed the follow NUTM1 fusion gene-associated sarcomas: [11]

In general, these NUTM1 fusion gene-associated sarcomas have very poor prognoses and require further study to determine of role of these fusion genes in the development and progression of their corresponding sarcomas. [11]

Related Research Articles

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Tumors of the hematopoietic and lymphoid tissues or tumours of the haematopoietic and lymphoid tissues are tumors that affect the blood, bone marrow, lymph, and lymphatic system. Because these tissues are all intimately connected through both the circulatory system and the immune system, a disease affecting one will often affect the others as well, making aplasia, myeloproliferation and lymphoproliferation closely related and often overlapping problems. While uncommon in solid tumors, chromosomal translocations are a common cause of these diseases. This commonly leads to a different approach in diagnosis and treatment of hematological malignancies. Hematological malignancies are malignant neoplasms ("cancer"), and they are generally treated by specialists in hematology and/or oncology. In some centers "hematology/oncology" is a single subspecialty of internal medicine while in others they are considered separate divisions. Not all hematological disorders are malignant ("cancerous"); these other blood conditions may also be managed by a hematologist.

<span class="mw-page-title-main">Acute lymphoblastic leukemia</span> Blood cancer characterised by overproduction of lymphoblasts

Acute lymphoblastic leukemia (ALL) is a cancer of the lymphoid line of blood cells characterized by the development of large numbers of immature lymphocytes. Symptoms may include feeling tired, pale skin color, fever, easy bleeding or bruising, enlarged lymph nodes, or bone pain. As an acute leukemia, ALL progresses rapidly and is typically fatal within weeks or months if left untreated.

<span class="mw-page-title-main">Oncovirus</span> Viruses that can cause cancer

An oncovirus or oncogenic virus is a virus that can cause cancer. This term originated from studies of acutely transforming retroviruses in the 1950–60s, when the term oncornaviruses was used to denote their RNA virus origin. With the letters RNA removed, it now refers to any virus with a DNA or RNA genome causing cancer and is synonymous with tumor virus or cancer virus. The vast majority of human and animal viruses do not cause cancer, probably because of longstanding co-evolution between the virus and its host. Oncoviruses have been important not only in epidemiology, but also in investigations of cell cycle control mechanisms such as the retinoblastoma protein.

<span class="mw-page-title-main">Undifferentiated pleomorphic sarcoma</span> Medical condition

Undifferentiated pleomorphic sarcoma (UPS), also termed pleomorphic myofibrosarcoma, high-grade myofibroblastic sarcoma, and high-grade myofibrosarcoma, is characterized by the World Health Organization (WHO) as a rare, poorly differentiated neoplasm. WHO classified it as one of the undifferentiated/unclassified sarcomas in the category of tumors of uncertain differentiation. Sarcomas are cancers derived mesenchymal stem cells that typically develop in bone, muscle, fat, blood vessels, lymphatic vessels, tendons, and ligaments. More than 70 sarcoma subtypes have been described. The UPS subtype of these sarcomas consists of tumor cells that are poorly differentiated and may appear as spindle-shaped cells, histiocytes, and giant cells. UPS is considered a diagnosis that defies formal sub-classification after thorough histologic, immunohistochemical, and ultrastructural examinations fail to identify the type of cells involved.

<span class="mw-page-title-main">Neprilysin</span> Mammalian protein found in Homo sapiens

Neprilysin is an enzyme that in humans is encoded by the MME gene. Neprilysin is a zinc-dependent metalloprotease that cleaves peptides at the amino side of hydrophobic residues and inactivates several peptide hormones including glucagon, enkephalins, substance P, neurotensin, oxytocin, and bradykinin. It also degrades the amyloid beta peptide whose abnormal folding and aggregation in neural tissue has been implicated as a cause of Alzheimer's disease. Synthesized as a membrane-bound protein, the neprilysin ectodomain is released into the extracellular domain after it has been transported from the Golgi apparatus to the cell surface.

<span class="mw-page-title-main">Ewing sarcoma</span> Type of cancer

Ewing sarcoma is a type of pediatric cancer that forms in bone or soft tissue. Symptoms may include swelling and pain at the site of the tumor, fever, and a bone fracture. The most common areas where it begins are the legs, pelvis, and chest wall. In about 25% of cases, the cancer has already spread to other parts of the body at the time of diagnosis. Complications may include a pleural effusion or paraplegia.

<span class="mw-page-title-main">ETV6</span> Protein-coding gene in the species Homo sapiens

ETV6 protein is a transcription factor that in humans is encoded by the ETV6 gene. The ETV6 protein regulates the development and growth of diverse cell types, particularly those of hematological tissues. However, its gene, ETV6 frequently suffers various mutations that lead to an array of potentially lethal cancers, i.e., ETV6 is a clinically significant proto-oncogene in that it can fuse with other genes to drive the development and/or progression of certain cancers. However, ETV6 is also an anti-oncogene or tumor suppressor gene in that mutations in it that encode for a truncated and therefore inactive protein are also associated with certain types of cancers.

<span class="mw-page-title-main">Mesoblastic nephroma</span> Medical condition

Congenital mesoblastic nephroma, while rare, is the most common kidney neoplasm diagnosed in the first three months of life and accounts for 3-5% of all childhood renal neoplasms. This neoplasm is generally non-aggressive and amenable to surgical removal. However, a readily identifiable subset of these kidney tumors has a more malignant potential and is capable of causing life-threatening metastases. Congenital mesoblastic nephroma was first named as such in 1967 but was recognized decades before this as fetal renal hamartoma or leiomyomatous renal hamartoma.

<span class="mw-page-title-main">BRD4</span> Protein-coding gene in the species Homo sapiens

Bromodomain-containing protein 4 is a protein that in humans is encoded by the BRD4 gene.

<span class="mw-page-title-main">Poroma</span>

Poromas are rare, benign, cutaneous adnexal tumors. Cutaneous adnexal tumors are a group of skin tumors consisting of tissues that have differentiated towards one or more of the four primary adnexal structures found in normal skin: hair follicles, sebaceous sweat glands, apocrine sweat glands, and eccrine sweat glands. Poromas are eccrine or apocrine sweat gland tumors derived from the cells in the terminal portion of these glands' ducts. This part of the sweat gland duct is termed the acrosyringium and had led to grouping poromas in the acrospiroma class of skin tumors. Here, poromas are regarded as distinct sweat gland tumors that differ from other sweat gland tumors by their characteristic clinical presentations, microscopic histopathology, and the genetic mutations that their neoplastic cells have recently been found to carry.

Porocarcinoma (PCA) is a rare form of skin cancer that develops in eccrine sweat glands, i.e. the body's widely distributed major type of sweat glands, as opposed to the apocrine sweat glands which are located primarily in the armpits and perineal area. This cancer typically develops in individuals as a single cutaneous tumor in the intraepidermal spiral part of these sweat glands' ducts at or near to where they open on the skin's surface. PCA tumors are classified as one form of the cutaneous adnexal tumors; in a study of 2,205 cases, PCA was the most common (11.8%) form of these tumors.

ETV6-NTRK3 gene fusion is the translocation of genetic material between the ETV6 gene located on the short arm of chromosome 12 at position p13.2 and the NTRK3 gene located on the long arm of chromosome 15 at position q25.3 to create the (12;15)(p13;q25) fusion gene, ETV6-NTRK3. This new gene consists of the 5' end of ETV6 fused to the 3' end of NTRK3. ETV6-NTRK3 therefore codes for a chimeric oncoprotein consisting of the helix-loop-helix (HLH) protein dimerization domain of the ETV6 protein fused to the tyrosine kinase domain of the NTRK3 protein. The ETV6 gene codes for the transcription factor protein, ETV6, which suppresses the expression of, and thereby regulates, various genes that in mice are required for normal hematopoiesis as well as the development and maintenance of the vascular network. NTRK3 codes for Tropomyosin receptor kinase C a NT-3 growth factor receptor cell surface protein that when bound to its growth factor ligand, neurotrophin-3, becomes an active tyrosine kinase that phosphorylates tyrosine residues on, and thereby stimulates, signaling proteins that promote the growth, survival, and proliferation of their parent cells. The tyrosine kinase of the ETV6-NTRK3 fusion protein is dysfunctional in that it is continuously active in phosphorylating tyrosine residues on, and thereby continuously stimulating, proteins that promote the growth, survival, and proliferation of their parent cells. In consequence, these cells take on malignant characteristics and are on the pathway of becoming cancerous. Indeed, the ETV6-NTRK3 fusion gene appears to be a critical driver of several types of cancers. It was originally identified in congenital fibrosarcoma and subsequently found in mammary secretory carcinoma, mammary analogue secretory carcinoma of salivary glands, salivary gland–type carcinoma of the thyroid, secretory carcinoma of the skin, congenital fibrosarcoma, congenital mesoblastic nephroma, rare cases of acute myelogenous leukemia, ALK-negative Inflammatory myofibroblastic tumour, cholangiocarcinoma, and radiation-induced papillary thyroid carcinoma.

<span class="mw-page-title-main">Low-grade fibromyxoid sarcoma</span> Medical condition

Low-grade fibromyxoid sarcoma (LGFMS) is a rare type of low-grade sarcoma first described by H. L. Evans in 1987. LGFMS are soft tissue tumors of the mesenchyme-derived connective tissues; on microscopic examination, they are found to be composed of spindle-shaped cells that resemble fibroblasts. These fibroblastic, spindle-shaped cells are neoplastic cells that in most cases of LGFMS express fusion genes, i.e. genes composed of parts of two different genes that form as a result of mutations. The World Health Organization (2020) classified LGFMS as a specific type of tumor in the category of malignant fibroblastic and myofibroblastic tumors.

<span class="mw-page-title-main">NUT carcinoma</span> Medical condition

NUT carcinoma is a rare genetically defined, very aggressive squamous cell epithelial cancer that usually arises in the midline of the body and is characterized by a chromosomal rearrangement in the nuclear protein in testis gene. In approximately 75% of cases, the coding sequence of NUTM1 in band 14 on the long arm of chromosome 15 is fused to BRD4 or BRD3, which creates a chimeric gene that encodes the BRD-NUT fusion protein. The remaining cases, the fusion of NUTM1 is to an unknown partner gene, usually called NUT-variant.

Mammary analogue secretory carcinoma (MASC), also termed MASCSG, is a salivary gland neoplasm. It is a secretory carcinoma which shares the microscopic pathologic features with other types of secretory carcinomas including mammary secretory carcinoma, secretory carcinoma of the skin, and salivary gland–type carcinoma of the thyroid. MASCSG was first described by Skálová et al. in 2010. The authors of this report found a chromosome translocation in certain salivary gland tumors, i.e. a (12;15)(p13;q25) fusion gene mutation. The other secretory carcinoma types carry this fusion gene.

<span class="mw-page-title-main">T-cell acute lymphoblastic leukemia</span> Type of acute lymphoblastic leukemia

T-cell acute lymphoblastic leukemia (T-ALL) is a type of acute lymphoblastic leukemia characterized by an aggressive malignant neoplasm of the bone marrow. Acute lymphoblastic leukemia (ALL) is a condition where immature white blood cells accumulate in the bone marrow, subsequently crowding out normal white blood cells and creating a build-up in the liver, spleen, and lymph nodes.

Sclerosing epithelioid fibrosarcoma (SEF) is a very rare malignant tumor of soft tissues that on microscopic examination consists of small round or ovoid neoplastic epithelioid fibroblast-like cells, i.e. cells that have features resembling both epithelioid cells and fibroblasts. In 2020, the World Health Organization classified SEF as a distinct tumor type in the category of malignant fibroblastic and myofibroblastic tumors. However, current studies have reported that low-grade fibromyxoid sarcoma (LGFMS) has many clinically and pathologically important features characteristic of SEF; these studies suggest that LGSFMS may be an early form of, and over time progress to become, a SEF. Since the World Health Organization has classified LGFMS as one of the malignant fibroblastic and myofibroblastic tumors that is distinctly different than SEF, SEF and LGFMS are here regarded as different tumor forms.

The FET protein family consists of three similarly structured and functioning proteins. They and the genes in the FET gene family which encode them are: 1) the EWSR1 protein encoded by the EWSR1 gene located at band 12.2 of the long arm of chromosome 22; 2) the FUS protein encoded by the FUS gene located at band 16 on the short arm of chromosome 16; and 3) the TAF15 protein encoded by the TAF15 gene located at band 12 on the long arm of chromosome 7 The FET in this protein family's name derives from the first letters of FUS, EWSR1, and TAF15.

CYLD cutaneous syndrome (CCS) encompasses three rare inherited cutaneous adnexal tumor syndromes: multiple familial trichoepithelioma (MFT1), Brooke–Spiegler syndrome (BSS), and familial cylindromatosis (FC). Cutaneous adnexal tumors are a large group of skin tumors that consist of tissues that have differentiated towards one of the four primary adnexal structures found in normal skin: hair follicles, sebaceous sweat glands, apocrine sweat glands, and eccrine sweat glands. CCS tumors are hair follicle tumors.

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